The hemopexin domain of MMP-9 inhibits angiogenesis and retards the growth of intracranial glioblastoma xenograft in nude mice.
Matrix Metalloproteinase-9 (MMP-9) consists of a prodomain, catalytic domain with 3 fibronectin-like type II modules and C-terminal hemopexin-like (PEX) domain. These domains play distinct roles in terms of proteolytic activity, substrate binding and interaction with inhibitors and receptors. To assess the potential of the MMP-9-PEX domain to interfere with tumor progression, we stably transfected human glioblastoma cells with an expression vector containing a cDNA sequence of the MMP-9-PEX. The selected clones exhibited decreased MMP-9 activity and reduced invasive capacity. We assessed how secretion of MMP-9-PEX by glioblastoma cells affects angiogenic capabilities of human microvascular endothelial cells (HMECs) in vitro. MMP-9-PEX conditioned medium treatment caused a reduction in migration of HMECs and inhibited capillary-like structure formation in association with suppression of vascular endothelial growth factor (VEGF) secretion and VEGF receptor-2 protein level. The suppression of HMECs survival by conditioned medium from MMP-9-PEX stable transfectants was associated with apoptosis induction characterized by an increase in cells with a sub-G0/G1 content, fragmentation of DNA, caspase-3, -8 and -9 activation and poly (ADP-ribose) polymerase (PARP) cleavage. A significant tumor growth inhibition was observed in intracranial implants of MMP-9-PEX stable transfectants in nude mice with attenuation of CD31 and MMP-9 protein expression. These results demonstrate that MMP-9-PEX inhibits angiogenic features of endothelial cells and retards intracranial glioblastoma growth.
Ezhilarasan
Ravesanker
R
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, IL 61656, USA.
Jadhav
Unmesh
U
Mohanam
Indra
I
Rao
Jasti S
JS
Gujrati
Meena
M
Mohanam
Sanjeeva
S
D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006466:Hemopexin / Q000737:chemistry*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D017434:Protein Structure, Tertiary
D006466:Hemopexin; D020780:Matrix Metalloproteinase 9